A Transcriptional Program Modulating Epithelial Death and Innate Function - Project 1

调节上皮死亡和先天功能的转录程序 - 项目 1

基本信息

批准号：
10631054
负责人：
Rama K Mallampalli
金额：
$ 43.2万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-03 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10631054
关键词：
Acetylation Acetyltransferase Acute Acute Lung Injury Acute Respiratory Distress Syndrome Amino Acids Attenuated Behavior Binding Biological Cell Death Cell Nucleus Cell Survival Cells Cellular biology Cessation of life Chemicals Clinical Coupled Critical Illness Cytoprotection Data Disease Distal Effector Cell Endotoxins Epigenetic Process Epithelial Cells Epithelium Equilibrium Exhibits Experimental Models Foundations Functional disorder Gene Silencing Genes Genetic Models Genetic Transcription Histone Acetylation Host Defense Human Immune Immune response Immunological Models Immunosuppression Impairment In Vitro Infection Inflammation Inflammatory Innate Immune Response Life Link Longevity Lung Lymphocyte Lysine Mediating Modeling Molecular Natural Immunity Nuclear Pathway interactions Patients Persons Pharmacotherapy Phase Play Pneumonia Pre-Clinical Model Prognosis Property Protein Biosynthesis Protein Dephosphorylation Proteins Proteolysis Pulmonary Inflammation Regulation Repression Role Sepsis Syndrome System Testing Transcription Coactivator Ubiquitin Ubiquitin-mediated Proteolysis Pathway alveolar epithelium antagonist design epigenetic marker fighting gene repression histone modification immune function in vivo inhibitor lung injury molecular modeling mortality novel opportunistic pathogen pharmacologic programs respiratory small molecule superinfection ubiquitin-protein ligase

项目摘要

Acute Respiratory Depress Syndrome (ARDS) can be a devastating disorder and prior studies have focused mainly on its hyper-inflammatory state. However, mounting data suggest that immune suppression partakes in this disorder, the molecular mechanisms of which remain unclear. This Project investigates a unique molecular model whereby a lysine acetyltransferase termed general control of amino acid synthesis protein 5-like 2 (Gcn5l2), normally targeted for its disposal in cells by a ubiquitin E3 ligase subunit, Fbxo24, executes alveolar epithelial cell death and suppression of genes involved in innate immunity through histone modification. Our hypothesis is that Gcn5l2, normally kept in check by ubiquitin- mediated degradation, is an endotoxin-responsive executioner of innate immune suppression and epithelial cellular death in experimental ARDS. As a corollary to this hypothesis, we propose that Gcn5l2 chemical inhibition will attenuate acetyltransferase activity. Hence, in this application we will first elucidate how endotoxin increases Gcn5l2 levels by abrogating its Fbxo24 E3 ubiquitin ligase mediated proteolysis in experimental lung injury (Aim 1). We will specifically investigate how Fbxo24 targets Gcn5l2 for its degradation using complementary in vitro and in vivo genetic models and then evaluate how endotoxin abrogates molecular interaction of these partners. Next, we will optimize the pharmacologic design and test a novel small molecule that exhibits distinct, and yet complementary immune modulatory and cytoprotective properties in 2-hit models of immune suppression and in an ex vivo isolated human lung system (Aim 2). These studies will provide a new pathobiologic model of immune dysregulation that will serve as a platform for generating small molecule modulators that optimize epithelial cell survival and restore host defense in subjects with severe critical illness.

急性呼吸抑制综合症 (ARDS) 可能是一种毁灭性的疾病，研究主要集中在其高炎症状态。然而，不断增加的数据表明免疫抑制参与了这种疾病，其分子机制目前尚不清楚。该项目研究了一种独特的分子模型，其中赖氨酸乙酰转移酶，称为氨基酸合成通用控制蛋白 5-like 2 (Gcn5l2)，通常通过泛素 E3 连接酶亚基 Fbxo24 在细胞中进行处理，执行肺泡上皮细胞死亡和先天免疫相关基因的抑制组蛋白修饰。我们的假设是 Gcn5l2，通常受到泛素的控制- 介导的降解，是先天免疫抑制的内毒素反应性刽子手和实验性 ARDS 中的上皮细胞死亡。作为这个假设的推论，我们提出 Gcn5l2 化学抑制会减弱乙酰转移酶活性。因此，在在本申请中，我们将首先阐明内毒素如何通过消除其作用来增加 Gcn5l2 水平 Fbxo24 E3 泛素连接酶介导实验性肺损伤中的蛋白水解（目标 1）。我们将特别研究 Fbxo24 如何利用互补性靶向 Gcn5l2 进行降解体外和体内遗传模型，然后评估内毒素如何消除分子这些合作伙伴的互动。接下来，我们将优化药理设计并进行测试新型小分子，表现出独特但互补的免疫调节和免疫抑制的 2 次打击模型和离体分离中的细胞保护特性人类肺系统（目标 2）。这些研究将提供一种新的免疫病理生物学模型失调，将作为生成小分子调节剂的平台优化重症患者的上皮细胞存活并恢复宿主防御疾病。